NF-?B inhibition in keratinocytes causes RIPK1-mediated necroptosis and skin inflammation

Tumor necrosis factor receptor 1 (TNFR1) activates NF-?B–dependent pro-inflammatory gene expression, but also induces cell death by triggering apoptosis and necroptosis. Inhibition of inhibitor NF-?B kinase (IKK)/NF-?B signaling in keratinocytes paradoxically unleashed spontaneous TNFR1-mediated skin inflammation mice, the underlying mechanisms remain poorly understood. Here, we show that TNFR1 causes mice with epidermis-specific knockout IKK2 inducing interacting protein (RIPK1)–dependent necroptosis, to a lesser extent apoptosis, keratinocytes. Combined ablation subunits RelA c-Rel caused keratinocyte Contrary currently established model inhibition transcription RIPK1-independent death, deficiency depended on RIPK1 activity. These results advance our understanding regulating TNFR1-induced identify RIPK1-mediated necroptosis as potent driver inflammation.